MEF2 expression linked to cognitive resilience in Alzheimer’s disease

Reuters Health - 09/11/2021 - Greater expression of the MEF2 protein was associated with cognitive resilience in mice and in analyses of brain tissue from cognitively resilient individuals versus nonresilient Alzheimer's disease patients, researchers report.

"We were excited that both mouse and human experiments pointed to an important role for the Mef2 family of transcription factors (TFs) in governing the cognitive benefits after environmental enrichment, and mediating cognitive resilience to neurodegenerative pathology," Dr. Li-Huei Tsai of the Massachusetts Institute of Technology in Cambridge told Reuters Health by email.

"The fact that environmental enrichment has been shown to have protective effects in numerous mouse models - including neurodegeneration, depression, and anxiety - suggests that the molecular features recruited after enrichment, such as Mef2, may shed therapeutic insights into other neuropsychiatric symptoms of Alzheimer's disease, beyond cognitive deficits," he said.

"Individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight," Dr. Tsai and colleagues state in their paper, published in Science Translation Medicine. "For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR."

Aiming to understand potential drivers of this phenomenon, the team began by profiling the molecular changes that arise from environmental enrichment in mice. This led to the identification of MEF2 TFs, and the finding that compared with mice raised in standard environments, those housed in environments enriched with toys and a running wheel had greater MEF2 expression.

The team also examined clinical and transcriptional data from more than 937 individuals with and without Alzheimer's disease, and found that cognitively resilient individuals had increased expression of MEF2; further, using single-cell RNA sequencing of human brain cells, they found that MEF2 appears to be most active in a subpopulation of excitatory neurons in the prefrontal cortex of resilient individuals.

The team then explored whether enhancing MEF2 could reverse symptoms of cognitive impairment in a mouse model of tauopathy. Engineering the mice to overexpress MEF2 was sufficient to improve cognitive flexibility and reduce hyperexcitability.

The authors conclude, "Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging."

Dr. Tsai added, "Our next research steps are to better understand the downstream factors that are regulated by Mef2 to facilitate enrichment. This might help elucidate additional therapeutic targets to promote cognitive resilience."

"We are also excited to mine our single-cell data from a cohort of resilient and non-resilient individuals to discover other drivers of neuroprotection in the face of AD pathology," he added.

Dr. Jason Krellman, Associate Professor of Neuropsychology at Columbia University Irving Medical Center in New York City commented in an email to Reuters Health, "The authors contend that MEF2 can protect against degenerative changes in the brain and/or buffer the brain against changes once they have begun. The findings are plausible and promising."

"The research reinforces the fact that cognitive stimulation is protective against the development and progression of cognitive deficits in neurodegenerative disease (and) identified one of likely many mechanisms by which cognitive stimulation provides protection inside the brain," he said.

"In doing so," he noted, "it identifies a potential target for medical therapies that could provide protection without the need for cognitive stimulation. This would mean that people who have not had the opportunity to receive high levels of education or work in cognitively demanding jobs over many years could get similar benefits from a medication or other treatment to boost natural protective mechanisms in the brain."

"However," he added, "medical therapy to boost natural neuroprotective mechanisms in the brain is still several years to decades away from becoming established and widely available, so staying cognitively active will likely still be one of the best ways of reducing risk of cognitive decline for some time to come."

SOURCE: https://bit.ly/3CWSVrg Science Translational Medicine, online November 3, 2021.

By Marilynn Larkin



Posted on 9 November 202116 November 2021